SummarySerotonin (5-HT) is a central neuromodulator and a major target of therapeutic psychoactive drugs, but relatively little is known about how it modulates information processing in neural circuits. The theory of predictive coding postulates that the brain combines raw bottom-up sensory information with top-down information from internal models to make perceptual inferences about the world. We hypothesize, based on preliminary data and prior literature, that a role of 5-HT in this process is to report prediction errors and promote the suppression and weakening of erroneous internal models. We propose that it does this by inhibiting top-down relative to bottom-up cortical information flow. To test this hypothesis, we propose a set of experiments in mice performing olfactory perceptual tasks. Our specific aims are: (1) We will test whether 5-HT neurons encode sensory prediction errors. (2) We will test their causal role in using predictive cues to guide perceptual decisions. (3) We will characterize how 5-HT influences the encoding of sensory information by neuronal populations in the olfactory cortex and identify the underlying circuitry. (4) Finally, we will map the effects of 5-HT across the whole brain and use this information to target further causal manipulations to specific 5-HT projections. We accomplish these aims using state-of-the-art optogenetic, electrophysiological and imaging techniques (including 9.4T small-animal functional magnetic resonance imaging) as well as psychophysical tasks amenable to quantitative analysis and computational theory. Together, these experiments will tackle multiple facets of an important general computational question, bringing to bear an array of cutting-edge technologies to address with unprecedented mechanistic detail how 5-HT impacts neural coding and perceptual decision-making.

Serotonin (5-HT) is a central neuromodulator and a major target of therapeutic psychoactive drugs, but relatively little is known about how it modulates information processing in neural circuits. The theory of predictive coding postulates that the brain combines raw bottom-up sensory information with top-down information from internal models to make perceptual inferences about the world. We hypothesize, based on preliminary data and prior literature, that a role of 5-HT in this process is to report prediction errors and promote the suppression and weakening of erroneous internal models. We propose that it does this by inhibiting top-down relative to bottom-up cortical information flow. To test this hypothesis, we propose a set of experiments in mice performing olfactory perceptual tasks. Our specific aims are: (1) We will test whether 5-HT neurons encode sensory prediction errors. (2) We will test their causal role in using predictive cues to guide perceptual decisions. (3) We will characterize how 5-HT influences the encoding of sensory information by neuronal populations in the olfactory cortex and identify the underlying circuitry. (4) Finally, we will map the effects of 5-HT across the whole brain and use this information to target further causal manipulations to specific 5-HT projections. We accomplish these aims using state-of-the-art optogenetic, electrophysiological and imaging techniques (including 9.4T small-animal functional magnetic resonance imaging) as well as psychophysical tasks amenable to quantitative analysis and computational theory. Together, these experiments will tackle multiple facets of an important general computational question, bringing to bear an array of cutting-edge technologies to address with unprecedented mechanistic detail how 5-HT impacts neural coding and perceptual decision-making.

Max ERC Funding

2 486 074 €

Duration

Start date: 2016-01-01, End date: 2020-12-31

Project acronymACTINIT

ProjectBrain-behavior forecasting: The causal determinants of spontaneous self-initiated action in the study of volition and the development of asynchronous brain-computer interfaces.

Summary"How are actions initiated by the human brain when there is no external sensory cue or other immediate imperative? How do subtle ongoing interactions within the brain and between the brain, body, and sensory context influence the spontaneous initiation of action? How should we approach the problem of trying to identify the neural events that cause spontaneous voluntary action? Much is understood about how the brain decides between competing alternatives, leading to different behavioral responses. But far less is known about how the brain decides "when" to perform an action, or "whether" to perform an action in the first place, especially in a context where there is no sensory cue to act such as during foraging. This project seeks to open a new chapter in the study of spontaneous voluntary action building on a novel hypothesis recently introduced by the applicant (Schurger et al, PNAS 2012) concerning the role of ongoing neural activity in action initiation. We introduce brain-behavior forecasting, the converse of movement-locked averaging, as an approach to identifying the neurodynamic states that commit the motor system to performing an action "now", and will apply it in the context of information foraging. Spontaneous action remains a profound mystery in the brain basis of behavior, in humans and other animals, and is also central to the problem of asynchronous intention-detection in brain-computer interfaces (BCIs). A BCI must not only interpret what the user intends, but also must detect "when" the user intends to act, and not respond otherwise. This remains the biggest challenge in the development of high-performance BCIs, whether invasive or non-invasive. This project will take a systematic and collaborative approach to the study of spontaneous self-initiated action, incorporating computational modeling, neuroimaging, and machine learning techniques towards a deeper understanding of voluntary behavior and the robust asynchronous detection of decisions-to-act."

"How are actions initiated by the human brain when there is no external sensory cue or other immediate imperative? How do subtle ongoing interactions within the brain and between the brain, body, and sensory context influence the spontaneous initiation of action? How should we approach the problem of trying to identify the neural events that cause spontaneous voluntary action? Much is understood about how the brain decides between competing alternatives, leading to different behavioral responses. But far less is known about how the brain decides "when" to perform an action, or "whether" to perform an action in the first place, especially in a context where there is no sensory cue to act such as during foraging. This project seeks to open a new chapter in the study of spontaneous voluntary action building on a novel hypothesis recently introduced by the applicant (Schurger et al, PNAS 2012) concerning the role of ongoing neural activity in action initiation. We introduce brain-behavior forecasting, the converse of movement-locked averaging, as an approach to identifying the neurodynamic states that commit the motor system to performing an action "now", and will apply it in the context of information foraging. Spontaneous action remains a profound mystery in the brain basis of behavior, in humans and other animals, and is also central to the problem of asynchronous intention-detection in brain-computer interfaces (BCIs). A BCI must not only interpret what the user intends, but also must detect "when" the user intends to act, and not respond otherwise. This remains the biggest challenge in the development of high-performance BCIs, whether invasive or non-invasive. This project will take a systematic and collaborative approach to the study of spontaneous self-initiated action, incorporating computational modeling, neuroimaging, and machine learning techniques towards a deeper understanding of voluntary behavior and the robust asynchronous detection of decisions-to-act."

Max ERC Funding

1 338 130 €

Duration

Start date: 2015-10-01, End date: 2020-09-30

Project acronymActiveCortex

ProjectActive dendrites and cortical associations

Researcher (PI)Matthew Larkum

Host Institution (HI)HUMBOLDT-UNIVERSITAET ZU BERLIN

Call DetailsAdvanced Grant (AdG), LS5, ERC-2014-ADG

SummaryConverging studies from psychophysics in humans to single-cell recordings in monkeys and rodents indicate that most important cognitive processes depend on both feed-forward and feedback information interacting in the brain. Intriguingly, feedback to early cortical processing stages appears to play a causal role in these processes. Despite the central nature of this fact to understanding brain cognition, there is still no mechanistic explanation as to how this information could be so pivotal and what events take place that might be decisive. In this research program, we will test the hypothesis that the extraordinary performance of the cortex derives from an associative mechanism built into the basic neuronal unit: the pyramidal cell. The hypothesis is based on two important facts: (1) feedback information is conveyed predominantly to layer 1 and (2) the apical tuft dendrites that are the major recipient of this feedback information are highly electrogenic.
The research program is divided in to several workpackages to systematically investigate the hypothesis at every level. As a whole, we will investigate the causal link between intrinsic cellular activity and behaviour. To do this we will use eletrophysiological and optical techniques to record and influence cell the intrinsic properties of cells (in particular dendritic activity) in vivo and in vitro in rodents. In vivo experiments will have a specific focus on context driven behaviour and in vitro experiments on the impact of long-range (feedback-carrying) fibers on cell activity. The study will also focus on synaptic plasticity at the interface of feedback information and dendritic electrogenesis, namely synapses on to the tuft dendrite of pyramidal neurons. The proposed program will not only address a long-standing and important hypothesis but also provide a transformational contribution towards understanding the operation of the cerebral cortex.

Converging studies from psychophysics in humans to single-cell recordings in monkeys and rodents indicate that most important cognitive processes depend on both feed-forward and feedback information interacting in the brain. Intriguingly, feedback to early cortical processing stages appears to play a causal role in these processes. Despite the central nature of this fact to understanding brain cognition, there is still no mechanistic explanation as to how this information could be so pivotal and what events take place that might be decisive. In this research program, we will test the hypothesis that the extraordinary performance of the cortex derives from an associative mechanism built into the basic neuronal unit: the pyramidal cell. The hypothesis is based on two important facts: (1) feedback information is conveyed predominantly to layer 1 and (2) the apical tuft dendrites that are the major recipient of this feedback information are highly electrogenic.
The research program is divided in to several workpackages to systematically investigate the hypothesis at every level. As a whole, we will investigate the causal link between intrinsic cellular activity and behaviour. To do this we will use eletrophysiological and optical techniques to record and influence cell the intrinsic properties of cells (in particular dendritic activity) in vivo and in vitro in rodents. In vivo experiments will have a specific focus on context driven behaviour and in vitro experiments on the impact of long-range (feedback-carrying) fibers on cell activity. The study will also focus on synaptic plasticity at the interface of feedback information and dendritic electrogenesis, namely synapses on to the tuft dendrite of pyramidal neurons. The proposed program will not only address a long-standing and important hypothesis but also provide a transformational contribution towards understanding the operation of the cerebral cortex.

SummaryThe project outlined here addresses the fundamental question how the brain encodes and controls behavior. While we have a reasonable understanding of the role of entire brain areas in such processes, and of mechanisms at the molecular and synaptic levels, there is a big gap in our knowledge of how behavior is controlled at the level of defined neuronal circuits.
In natural environments, chances for survival depend on learning about possible aversive and appetitive outcomes and on the appropriate behavioral responses. Most studies addressing the underlying mechanisms at the level of neuronal circuits have focused on aversive learning, such as in Pavlovian fear conditioning. Understanding how activity in defined neuronal circuits mediates appetitive learning, as well as how these circuitries are shared and interact with aversive learning circuits, is a central question in the neuroscience of learning and memory and the focus of this grant application.
Using a multidisciplinary approach in mice, combining behavioral, in vivo and in vitro electrophysiological, imaging, optogenetic and state-of-the-art viral circuit tracing techniques, we aim at dissecting the neuronal circuitry of appetitive Pavlovian conditioning with a focus on the amygdala, a key brain region important for both aversive and appetitive learning. Ultimately, elucidating these mechanisms at the level of defined neurons and circuits is fundamental not only for an understanding of memory processes in the brain in general, but also to inform a mechanistic approach to psychiatric conditions associated with amygdala dysfunction and dysregulated emotional responses including anxiety and mood disorders.

The project outlined here addresses the fundamental question how the brain encodes and controls behavior. While we have a reasonable understanding of the role of entire brain areas in such processes, and of mechanisms at the molecular and synaptic levels, there is a big gap in our knowledge of how behavior is controlled at the level of defined neuronal circuits.
In natural environments, chances for survival depend on learning about possible aversive and appetitive outcomes and on the appropriate behavioral responses. Most studies addressing the underlying mechanisms at the level of neuronal circuits have focused on aversive learning, such as in Pavlovian fear conditioning. Understanding how activity in defined neuronal circuits mediates appetitive learning, as well as how these circuitries are shared and interact with aversive learning circuits, is a central question in the neuroscience of learning and memory and the focus of this grant application.
Using a multidisciplinary approach in mice, combining behavioral, in vivo and in vitro electrophysiological, imaging, optogenetic and state-of-the-art viral circuit tracing techniques, we aim at dissecting the neuronal circuitry of appetitive Pavlovian conditioning with a focus on the amygdala, a key brain region important for both aversive and appetitive learning. Ultimately, elucidating these mechanisms at the level of defined neurons and circuits is fundamental not only for an understanding of memory processes in the brain in general, but also to inform a mechanistic approach to psychiatric conditions associated with amygdala dysfunction and dysregulated emotional responses including anxiety and mood disorders.

Max ERC Funding

2 497 200 €

Duration

Start date: 2016-01-01, End date: 2020-12-31

Project acronymBrain circRNAs

ProjectRounding the circle: Unravelling the biogenesis, function and mechanism of action of circRNAs in the Drosophila brain.

Researcher (PI)Sebastian Kadener

Host Institution (HI)THE HEBREW UNIVERSITY OF JERUSALEM

Call DetailsConsolidator Grant (CoG), LS5, ERC-2014-CoG

SummaryTight regulation of RNA metabolism is essential for normal brain function. This includes co and post-transcriptional regulation, which are extremely prevalent in neurons. Recently, circular RNAs (circRNAs), a highly abundant new type of regulatory non-coding RNA have been found across the animal kingdom. Two of these RNAs have been shown to act as miRNA sponges but no function is known for the thousands of other circRNAs, indicating the existence of a widespread layer of previously unknown gene regulation.
The present proposal aims to comprehensively determine the role and mode of actions of circRNAs in gene expression and RNA metabolism in the fly brain. We will do so by studying their biogenesis, transport, and mechanism of action, as well as by determining the roles of circRNAs in neuronal function and behaviour. Briefly, we will: 1) identify factors involved in the biogenesis, localization, and stabilization of circRNAs; 2) determine neuro-developmental, molecular, neural and behavioural phenotypes associated with down or up regulation of specific circRNAs; 3) study the molecular mechanisms of action of circRNAs: identify circRNAs that work as miRNA sponges and determine whether circRNAs can encode proteins or act as signalling molecules and 4) perform mechanistic studies in order to determine cause-effect relationships between circRNA function and brain physiology and behaviour.
The present proposal will reveal the key pathways by which circRNAs control gene expression and influence neuronal function and behaviour. Therefore it will be one of the pioneer works in the study of this new and important area of research, which we predict will fundamentally transform the study of gene expression regulation in the brain

Tight regulation of RNA metabolism is essential for normal brain function. This includes co and post-transcriptional regulation, which are extremely prevalent in neurons. Recently, circular RNAs (circRNAs), a highly abundant new type of regulatory non-coding RNA have been found across the animal kingdom. Two of these RNAs have been shown to act as miRNA sponges but no function is known for the thousands of other circRNAs, indicating the existence of a widespread layer of previously unknown gene regulation.
The present proposal aims to comprehensively determine the role and mode of actions of circRNAs in gene expression and RNA metabolism in the fly brain. We will do so by studying their biogenesis, transport, and mechanism of action, as well as by determining the roles of circRNAs in neuronal function and behaviour. Briefly, we will: 1) identify factors involved in the biogenesis, localization, and stabilization of circRNAs; 2) determine neuro-developmental, molecular, neural and behavioural phenotypes associated with down or up regulation of specific circRNAs; 3) study the molecular mechanisms of action of circRNAs: identify circRNAs that work as miRNA sponges and determine whether circRNAs can encode proteins or act as signalling molecules and 4) perform mechanistic studies in order to determine cause-effect relationships between circRNA function and brain physiology and behaviour.
The present proposal will reveal the key pathways by which circRNAs control gene expression and influence neuronal function and behaviour. Therefore it will be one of the pioneer works in the study of this new and important area of research, which we predict will fundamentally transform the study of gene expression regulation in the brain

Max ERC Funding

1 971 750 €

Duration

Start date: 2016-02-01, End date: 2021-01-31

Project acronymBRAINCOMPATH

ProjectMesoscale Brain Dynamics: Computing with Neuronal Pathways

Researcher (PI)Fritjof Helmchen

Host Institution (HI)UNIVERSITAT ZURICH

Call DetailsAdvanced Grant (AdG), LS5, ERC-2014-ADG

SummaryBrain computations rely on proper signal flow through the complex network of connected brain regions. Despite a wealth of anatomical and functional data – from microscopic to macroscopic scale – we still poorly understand the principles of how signal flow is routed through neuronal networks to generate appropriate behavior. Brain dynamics on the 'mesoscopic' scale, the intermediate level where local microcircuits communicate via axonal pathways, has remained a particular blind spot of research as it has been difficult to access under in vivo conditions. Here, I propose to tackle the mesoscopic level of brain dynamics both experimentally and theoretically, adopting a fresh perspective centered on neuronal pathway dynamics. Experimentally, we will utilize and further advance state-of-the-art genetic and optical techniques to create a toolbox for measuring and manipulating signal flow in pathway networks across a broad range of temporal scales. In particular, we will improve fiber-optic based methods for probing the activity of either individual or multiple neuronal pathways with high specificity. Using these tools we will set out to reveal mesoscopic brain dynamics across relevant cortical and subcortical regions in awake, behaving mice. Specifically, we will investigate sensorimotor learning for a reward-based texture discrimination task and rapid sensorimotor control during skilled locomotion. Moreover, by combining fiber-optic methods with two-photon microscopy and fMRI, respectively, we will start linking the meso-level to the micro- and macro-levels. Throughout the project, experiments will be complemented by computational approaches to analyse data, model pathway dynamics, and conceptualize a formal theory of mesoscopic dynamics. This project may transform the field by bridging the hierarchical brain levels and opening significant new avenues to assess physiological as well as pathological signal flow in the brain.

Brain computations rely on proper signal flow through the complex network of connected brain regions. Despite a wealth of anatomical and functional data – from microscopic to macroscopic scale – we still poorly understand the principles of how signal flow is routed through neuronal networks to generate appropriate behavior. Brain dynamics on the 'mesoscopic' scale, the intermediate level where local microcircuits communicate via axonal pathways, has remained a particular blind spot of research as it has been difficult to access under in vivo conditions. Here, I propose to tackle the mesoscopic level of brain dynamics both experimentally and theoretically, adopting a fresh perspective centered on neuronal pathway dynamics. Experimentally, we will utilize and further advance state-of-the-art genetic and optical techniques to create a toolbox for measuring and manipulating signal flow in pathway networks across a broad range of temporal scales. In particular, we will improve fiber-optic based methods for probing the activity of either individual or multiple neuronal pathways with high specificity. Using these tools we will set out to reveal mesoscopic brain dynamics across relevant cortical and subcortical regions in awake, behaving mice. Specifically, we will investigate sensorimotor learning for a reward-based texture discrimination task and rapid sensorimotor control during skilled locomotion. Moreover, by combining fiber-optic methods with two-photon microscopy and fMRI, respectively, we will start linking the meso-level to the micro- and macro-levels. Throughout the project, experiments will be complemented by computational approaches to analyse data, model pathway dynamics, and conceptualize a formal theory of mesoscopic dynamics. This project may transform the field by bridging the hierarchical brain levels and opening significant new avenues to assess physiological as well as pathological signal flow in the brain.

SummaryThe brain is an extraordinary complex assembly of neuronal and glial cells that underpins cognitive functions. How adequate numbers of these cells are generated by neural stem cells in embryonic and early postnatal development and how they distribute and interconnect within brain tissue is still debated. In particular, the potentialities of individual neural stem cells, their potential heterogeneity and the mechanisms regulating their function are still poorly characterized in situ; likewise, the clonal architecture of mature brain tissue and its influence on neural circuitry are only partially explored. Deciphering these aspects is essential to link neural circuit development, structure and function, and to understand the aetiology of neurodevelopmental disorders.
We have recently established transgenic strategies to simultaneously track the lineage of multiple individual neural stem cells in the intact developing brain and experimentally perturb their development. We will use these approaches in combination with recent large-volume imaging methods for high-throughput analysis of individual neural and glial clones in the mouse cortex. This will allow us to assay neural progenitor potentialities and equivalence, characterize developmental changes occurring in the neurogenic niche, describe the clonal organization of the mature cortex and study its link with neural connectivity. To decipher intrinsic and extrinsic mechanisms regulating neural progenitor activity and understand how they produce appropriate numbers of cells, we will assay the outcome of functional perturbations targeting key steps of neural development, introduced in precursors or in their local environment. These experiments will reveal how neural stem cell output might be regulated by cell interactions and intercellular signals. This multidisciplinary project will set the basis for quantitative analysis of brain development with single-cell resolution in normal and pathological conditions.

The brain is an extraordinary complex assembly of neuronal and glial cells that underpins cognitive functions. How adequate numbers of these cells are generated by neural stem cells in embryonic and early postnatal development and how they distribute and interconnect within brain tissue is still debated. In particular, the potentialities of individual neural stem cells, their potential heterogeneity and the mechanisms regulating their function are still poorly characterized in situ; likewise, the clonal architecture of mature brain tissue and its influence on neural circuitry are only partially explored. Deciphering these aspects is essential to link neural circuit development, structure and function, and to understand the aetiology of neurodevelopmental disorders.
We have recently established transgenic strategies to simultaneously track the lineage of multiple individual neural stem cells in the intact developing brain and experimentally perturb their development. We will use these approaches in combination with recent large-volume imaging methods for high-throughput analysis of individual neural and glial clones in the mouse cortex. This will allow us to assay neural progenitor potentialities and equivalence, characterize developmental changes occurring in the neurogenic niche, describe the clonal organization of the mature cortex and study its link with neural connectivity. To decipher intrinsic and extrinsic mechanisms regulating neural progenitor activity and understand how they produce appropriate numbers of cells, we will assay the outcome of functional perturbations targeting key steps of neural development, introduced in precursors or in their local environment. These experiments will reveal how neural stem cell output might be regulated by cell interactions and intercellular signals. This multidisciplinary project will set the basis for quantitative analysis of brain development with single-cell resolution in normal and pathological conditions.

SummaryAn expanded GGGGCC repeat in a non-coding region of the C9orf72 gene is the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The repeat RNA is transcribed and accumulates in neuronal RNA aggregates, implicating RNA toxicity as a key pathogenic mechanism. However, the pathways that lead to neurodegeneration are unknown. My lab has made pioneering contributions to the understanding of C9orf72 FTD/ALS, and reported the first structure of the repeat RNA, and the first description of both sense and antisense RNA aggregates in patient brain. We have now developed new disease models that allow, for the first time, the dissection of RNA toxicity both in vivo and in sophisticated neuronal culture models. We have also used our knowledge of the repeat structure to identify novel small molecules that show very strong binding to the repeats. We will utilise our innovative disease models in a multidisciplinary approach to fully dissect the cellular pathways underlying C9orf72 repeat RNA toxicity in vivo, on a genome-wide scale. Altered RNA metabolism has been implicated in a wide range of neurodegenerative diseases, indicating that our findings will provide profound new insight into fundamental mechanisms of neuronal maintenance and survival. This research programme will also deliver a step change in our understanding of C9orf72 FTD/ALS pathogenesis and provide essential insight for the identification of small molecules with genuine therapeutic potential. RNA-mediated mechanisms are now known to be a common theme in neurodegeneration, suggesting these findings will have broad significance.

An expanded GGGGCC repeat in a non-coding region of the C9orf72 gene is the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The repeat RNA is transcribed and accumulates in neuronal RNA aggregates, implicating RNA toxicity as a key pathogenic mechanism. However, the pathways that lead to neurodegeneration are unknown. My lab has made pioneering contributions to the understanding of C9orf72 FTD/ALS, and reported the first structure of the repeat RNA, and the first description of both sense and antisense RNA aggregates in patient brain. We have now developed new disease models that allow, for the first time, the dissection of RNA toxicity both in vivo and in sophisticated neuronal culture models. We have also used our knowledge of the repeat structure to identify novel small molecules that show very strong binding to the repeats. We will utilise our innovative disease models in a multidisciplinary approach to fully dissect the cellular pathways underlying C9orf72 repeat RNA toxicity in vivo, on a genome-wide scale. Altered RNA metabolism has been implicated in a wide range of neurodegenerative diseases, indicating that our findings will provide profound new insight into fundamental mechanisms of neuronal maintenance and survival. This research programme will also deliver a step change in our understanding of C9orf72 FTD/ALS pathogenesis and provide essential insight for the identification of small molecules with genuine therapeutic potential. RNA-mediated mechanisms are now known to be a common theme in neurodegeneration, suggesting these findings will have broad significance.

Max ERC Funding

1 985 699 €

Duration

Start date: 2015-10-01, End date: 2020-09-30

Project acronymCHIME

ProjectThe Role of Cortico-Hippocampal Interactions during Memory Encoding

Researcher (PI)Daniel (Ari) Bendor

Host Institution (HI)UNIVERSITY COLLEGE LONDON

Call DetailsStarting Grant (StG), LS5, ERC-2014-STG

SummaryThis research proposal’s goal is to investigate the role of cortico-hippocampal interactions during the encoding and consolidation of a memory. Current memory consolidation models postulate that memory storage in our brains occurs by a dynamic process- a recent episodic experience is initially encoded in the hippocampus, and during off-line states such as sleep, the encoded memory is gradually transferred to neocortex for long-term storage. One potential neural mechanism by which this could occur is replay, a phenomenon where neural activity patterns in the hippocampus evoked by a previous experience reactivate spontaneously during non-REM sleep, leading to coordinated cortical reactivation. While previous work suggests that hippocampal replay is important for encoding new memories, how memory consolidation is accomplished through cortico-hippocampal interactions is not well understood.
This research project has three major aims- 1) examine how cortical feedback influences which spatial trajectory is replayed by the hippocampus, 2) investigate how the hippocampal replay of a behavioural episode modifies cortical circuits, 3) measure the causal role of cortico-hippocampal interactions in consolidating memories. We will record ensemble activity from freely moving rats during an auditory-spatial association task and during post-behavioural sleep sessions. We will focus our ensemble recordings on two brain regions: 1) the dorsal CA1 region of the hippocampus, where the phenomenon of sleep replay has been most extensively examined, and 2) auditory cortex, a region of the brain critical for both auditory perception and long-term memory storage. This work will use behavioral and molecular-genetic techniques in combination with large-scale electrophysiological recordings, to help elucidate the role of cortico-hippocampal interactions in memory encoding and consolidation.

This research proposal’s goal is to investigate the role of cortico-hippocampal interactions during the encoding and consolidation of a memory. Current memory consolidation models postulate that memory storage in our brains occurs by a dynamic process- a recent episodic experience is initially encoded in the hippocampus, and during off-line states such as sleep, the encoded memory is gradually transferred to neocortex for long-term storage. One potential neural mechanism by which this could occur is replay, a phenomenon where neural activity patterns in the hippocampus evoked by a previous experience reactivate spontaneously during non-REM sleep, leading to coordinated cortical reactivation. While previous work suggests that hippocampal replay is important for encoding new memories, how memory consolidation is accomplished through cortico-hippocampal interactions is not well understood.
This research project has three major aims- 1) examine how cortical feedback influences which spatial trajectory is replayed by the hippocampus, 2) investigate how the hippocampal replay of a behavioural episode modifies cortical circuits, 3) measure the causal role of cortico-hippocampal interactions in consolidating memories. We will record ensemble activity from freely moving rats during an auditory-spatial association task and during post-behavioural sleep sessions. We will focus our ensemble recordings on two brain regions: 1) the dorsal CA1 region of the hippocampus, where the phenomenon of sleep replay has been most extensively examined, and 2) auditory cortex, a region of the brain critical for both auditory perception and long-term memory storage. This work will use behavioral and molecular-genetic techniques in combination with large-scale electrophysiological recordings, to help elucidate the role of cortico-hippocampal interactions in memory encoding and consolidation.

Max ERC Funding

1 500 000 €

Duration

Start date: 2015-04-01, End date: 2020-03-31

Project acronymCIRCUITASSEMBLY

ProjectDevelopment of functional organization of the visual circuits in mice

Researcher (PI)Keisuke Yonehara

Host Institution (HI)AARHUS UNIVERSITET

Call DetailsStarting Grant (StG), LS5, ERC-2014-STG

SummaryThe key organizing principles that characterize neuronal systems include asymmetric, parallel, and topographic connectivity of the neural circuits. The main aim of my research is to elucidate the key principles underlying functional development of neural circuits by focusing on those organizing principles. I choose mouse visual system as my model since it contains all of these principles and provides sophisticated genetic tools to label and manipulate individual circuit components. My research is based on the central hypothesis that the mechanisms of brain development cannot be fully understood without first identifying individual functional cell types in adults, and then understanding how the functions of these cell types become established, using cell-type-specific molecular and synaptic mechanisms in developing animals. Recently, I have identified several transgenic mouse lines in which specific cell types in a visual center, the superior colliculus, are labeled with Cre recombinase in both developing and adult animals. Here I will take advantage of these mouse lines to ask fundamental questions about the functional development of neural circuits. First, how are distinct sensory features processed by the parallel topographic neuronal pathways, and how do they contribute to behavior? Second, what are the molecular and synaptic mechanisms that underlie developmental circuit plasticity for forming parallel topographic neuronal maps in the brain? Third, what are the molecular mechanisms that set up spatially asymmetric circuit connectivity without the need for sensory experience? I predict that my insights into the developmental mechanism of asymmetric, parallel, and topographic connectivity and circuit plasticity will be instructive when studying other brain circuits which contain similar organizing principles.

The key organizing principles that characterize neuronal systems include asymmetric, parallel, and topographic connectivity of the neural circuits. The main aim of my research is to elucidate the key principles underlying functional development of neural circuits by focusing on those organizing principles. I choose mouse visual system as my model since it contains all of these principles and provides sophisticated genetic tools to label and manipulate individual circuit components. My research is based on the central hypothesis that the mechanisms of brain development cannot be fully understood without first identifying individual functional cell types in adults, and then understanding how the functions of these cell types become established, using cell-type-specific molecular and synaptic mechanisms in developing animals. Recently, I have identified several transgenic mouse lines in which specific cell types in a visual center, the superior colliculus, are labeled with Cre recombinase in both developing and adult animals. Here I will take advantage of these mouse lines to ask fundamental questions about the functional development of neural circuits. First, how are distinct sensory features processed by the parallel topographic neuronal pathways, and how do they contribute to behavior? Second, what are the molecular and synaptic mechanisms that underlie developmental circuit plasticity for forming parallel topographic neuronal maps in the brain? Third, what are the molecular mechanisms that set up spatially asymmetric circuit connectivity without the need for sensory experience? I predict that my insights into the developmental mechanism of asymmetric, parallel, and topographic connectivity and circuit plasticity will be instructive when studying other brain circuits which contain similar organizing principles.